C. difficile (or C. diff) is a Gram-positive, spore-forming, anaerobic bacterium that represents the leading cause of nosocomial (hospital-acquired) antibiotic-associated diarrhea and pseudomembranous colitis. C. difficile infection is estimated to total more than 750,000 cases per year in the U.S., and it is responsible for more deaths than all other intestinal infections combined (1). In many hospitals, C. difficile constitutes a greater risk to patients than methicillin-resistant Staphylococcus aureus (MRSA) or any other bacteria (2). The annual costs for management of Clostridium difficile-associated disease (CDAD) are estimated to exceed 3.2 billion dollars in the U.S. (3). Recent outbreaks of C. difficile strains with increased virulence or antibiotic resistance have led to treatment failures, more frequent relapses and increased mortality rates (4).
CDAD is typically induced by the disruption of the colonic flora through the use of antibiotics such as clindamycin, cephalosporins, and fluoroquinolones.(3,8) This perturbation in the colonic microenvironment, along with exposure to C. difficile spores, leads to colonization. Approximately one-third of all patients that become colonized develop CDAD(9), which can result in severe diarrhea, perforation of the colon, colectomy and death (10). CDAD results following the acquisition and proliferation of C. difficile in the gut, where C. difficile bacteria produce toxin A and toxin B, two important virulence factors of CDAD. Toxins A and B of C. difficile show considerable sequence and structural homology. Both have a C-terminal receptor-binding domain containing multiple repeating sequences, a central hydrophobic domain and an N-terminal glucosyltransferase domain. The receptor-binding domain mediates binding of the toxins to intestinal epithelial cells via host receptors that remain poorly defined in humans. Following internalization via an endosomal pathway, the central hydrophobic domain inserts into the membrane of the endosome. The acidic pH of the endosome triggers pore formation and translocation of the amino-terminal domains of the toxins into the cytosol. Glucosylation of the cytosolic target Rho GTPases leads to disruption of the cytoskeleton and cell death. Toxins A and B demonstrate different pathological profiles with potential synergy in causing disease.
Recent outbreaks of a hypervirulent strain of C. difficile have resulted in increased rates of severe disease, more frequent relapses, and increased mortality. One hypervirulent strain, BI/NAP1/027 toxintoype III, was historically uncommon, but is now epidemic. Hypervirulent strains, such as B1/NAP1/027, produce several times more toxin A and toxin B than non-hypervirulent strains of C. difficile, making such strains more formidable to treat following infection. Since resistance of hypervirulent strains to commonly-used antimicrobials and antibiotics is a growing problem that makes these strains more difficult to treat and contain, additional treatment approaches and more potent therapies are needed to combat hypervirulence and the recurrence of disease that is associated with hypervirulent C. difficile isolates.
Current antibiotic treatments for C. difficile infection include the use of vancomycin and/or metronidazole; however these antibiotics are limited by incomplete response rates and increasing reinfection and recurrence rates. Since 2000, substantially higher failure rates have been reported for metronidazole therapy (23-25). The high recurrence rates following antibiotic treatment may result from continued disruption of the normal colonic flora, giving C. difficile the opportunity to recover with little competition.(26-28) The risk of recurrence is increased in patients who have already had one recurrence, rising from about 20% after an initial episode to more than 60% after two or more recurrences.(29,30) This increased risk of recurrence has been associated with the failure to mount an adequate antitoxin antibody response.(31) Indeed, patients with the highest titers of serum IgG antitoxin at the end of antimicrobial therapy had a decreased risk of recurrence.(32) In a separate study, serum anti-toxin B antibody levels were correlated with protection from recurrent CDAD.(33)
The prevalence of C. difficile infection has been increasing steadily, particularly in the elderly, who are often frail. Approximately one-third of patients with C. difficile infection have recurrences of their infection, usually within two months of the initial illness. Repeat infections tend to be more severe than the original disease; they are often more fatal. Older adults and people with weakened immune systems are particularly susceptible to recurring infections. If not treated promptly and appropriately, the complications of C. difficile infection include dehydration, kidney failure, bowel perforation, toxic megacolon, which can lead to rupture of the colon, and death.
Although in the United States, C. difficile infection is the most common infection acquired by hospitalized patients, it may also be acquired outside of hospitals in the community. It is estimated that 20,000 infections with C. difficile occur in the community each year in the United States. Internationally, the incidence is highly variable and depends on multiple factors, including the frequency with which endoscopy is used to establish the diagnosis, antimicrobial use patterns and epidemiologic patterns.
Thus, it is clear that disease caused by C. difficile infection puts the lives of people of all ages in jeopardy, both in nosocomial settings and in the community at large. In today's world, there is an ever present risk of C. difficile infection for those who face hospitalization or who are in long-term hospital care. Because there is also a chance of contracting C. difficile infection outside of a hospital environment, the possibility of young children and babies contracting the disease is great. In addition, there is a potential that current antibiotic regimens used to treat C. difficile may be less than optimally effective. Patients who present with C. difficile-associated disease require extensive in-patient care and a long duration hospital stay. The costs associated with the high degree of supportive hospital care and treatment needed for C. difficile-associated disease patients are large and involve expensive resources, such as greater numbers of physician and nursing staffing, laboratory testing and monitoring, concomitant medications and additional supportive measures.
Consequently, there is a need for more effective medications, drugs and treatments that target the life-threatening diseases caused by C. difficile, and, in particular the potent toxins that are produced by C. difficile, for prophylactic and therapeutic benefit. There is an unmet medical need for successful and lasting treatments for C. difficile-associated disease that offer lower potential for developing resistance and higher potential for successful patient response and disease resolution, leading to disease eradication.